Hyponatremia causes

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Saeedeh Kowsarnia M.D.[2]

Overview

Hyponatremia is caused by either increase ADH action/ secretion or kidney function impairment. SIAD is the most common cause of euvolemic hyponatremia. After SIAD, polydipsia, drugs and clinical disorders are the most encountered etiologies in clinical practice.

Causes

To review the mechanisms of developing hyponatremia, click here.

• Etiologies of SIAD:

Conditions
Malignant disorders	Carcinoma: Lung ( small cell carcinoma, mesothelioma), oropharynx, stomach, duodenum, pancreas, ureter, bladder, prostate, endometrium, thymoma Lymphomas Sarcomas: Ewing's sarcoma Olfactory neuroblastoma
Pulmonary diseases	Infections: Bacterial pneumonia, viral pneumonia, pulmonary abscess, tuberculosis, aspergillosis Others: Asthma, cystic fibrosis, respiratory failure, emphysema, COPD,coronavirus disease, positive-pressure ventilation
CNS disorders	Infections: Encephalitis, meningitis, brain abscess, RMSF, AIDS, malaria Vascular and SOP: Subarachnoid hemorrhage, stroke, brain tumors, head trauma Others: Hydrocephalus, cavernous sinus thrombosis, Multiple sclerosis, Guillain–Barré syndrome, Shy–Drager syndrome, delirium tremens, acute intermittent porphyria, chronic psychosis, pituitary stalk section, transsphenoidal adenomectomy
Other causes	Hereditary: Gain-of-function mutation of V2 receptors Idiopathic Drugs Transient: Exercise, general anesthesia, nausea, pain, stress

• Causes of acute hyponatremia: (develops in < 48 hrs)

Etiology
Post operative phase Transurethral or endoscopic procedure (mannitol, sorbitol, glycine) Colonoscopy preparation  Polydipsia Exercise Oxytocin Cyclophosphamide Ecstasy( 3,4-Methylenedioxymethamphetamine, MDMA) Thiazide Halopridol Recently started desmopressin, terlipressin, vasopressin

( Etiologies that cause hyperacute and acute hyponatremia are applicable to each category interchangeably depending on the onset of symptoms)

• Causes of Hyponatremia based upon Serum Osmolality:

Classification	Serum Osmolality	Etiology
Hypertonic or Isotonic Hyponatremia	> 295 mOsm/kg	Hyperglycemia‡, Mannitol, Glycine, Maltose, severe azotemia
Isotonic Hyponatremia (Pseudohyponatremia)	275 – 295 mOsm/kg	Lab/blood draw error, Post TURP (bladder irrigation with osmotic solutions), intravenous immunoglobulin (IVIg), Hyperlipidemia ( triglyceride, cholesterol ), hyper paraproteinemia (monoclonal gammopathy of undetermined significance (MGUS), multiple myeloma),
Hypotonic Hyponatremia	< 275 mOsm/kg	Glycerol, Sorbitol, Etiology depends upon volume status (Hypervolemic/ Euvolemic/ Hypovolemic)
Alcohol, Urea, Ethylen glycol are ineffective osmoles, cause hyperosmolar isotonic serum but not hyponatremia.

‡ Hyperglycemia causes osmotic diuresis results in a rise in serum sodium concentration, on the other hand it leads to extracellular shift of water due to osmotic gradient which causes relative hyponatremia , depends on which effect is stronger, there would be hypertonicity or hypotonicity.   

• Causes of Hyponatremia based on volume status  :

Volume status	Sodium status	Causes
Hypovolemic Hyponatremia	total body water ↓ total body sodium ↓↓	GI loss: Vomiting, diarrhea, tube drainage Insensible loss: Sweating, burns Renal loss: Salt-wasting nephropathy (inappropriate loss of Na+-Cl– in the urine), bicarbonaturia ( renal tubular acidosis, metabolic alkalosis), osmotic diuresis, diuretic use, cerebral salt-wasting syndrome (Stroke ,SAH ,↑ brain natriuretic peptide and ↑ renal sodium loss ) Third spacing of fluids : Pancreatitis, hypoalbuminemia, Small bowel obstruction Mineralocorticoid deficiency: Addison disease (primary) Excessive diuretic administration: mostly thiazide diuretics
Hypervolemic Hyponatremia	total body water ↑↑ total body sodium ↑	Renal disease: Acute or chronic kidney disease or injury (due to relatively higher water versus salt intake and poor excretion), nephrotic syndrome Congestive heart failure Cirrhosis Iatrogenic
Euvolemic Hyponatremia	total body water ↑ total body sodium ↔	Drugs: Vasopressin, diuretics, antidepressants, opioids SIAD: SIADH (Malignancy, central nervous system (CNS) disorders, pulmonary disease, or drugs, postoperative nausea, pain, stress, neoplasia (common), trauma, pregnancy) , nephrogenic SIAD (Gain-of-function mutation of v2 receptors) High fluid intake: Physical activity, surgery, primary polydipsia, potomania, tea & toast diet (caused by a low intake of solutes with relatively high fluid intake) Medical testing (excess fluid intake) :Colonoscopy or cardiac catheterization Hypothyroidism Hormonal: Glucocorticoid deficiency, pituitary failure (secondary), hypothalamic failure (tertiary) Reset osmostat † : Drugs, pregnancy Iatrogenic

† Altered sensitivity to serum osmolality by the hypothalamic osmoreceptors

• Drugs which cause hyponatremia:

Drug Mechanisms	Drug Classification
Increase ADH secretion	Antidepressants:Tricyclic antidepressants ( Amitryptiline, Protriptyline, Desipramine),Selective serotonin reuptake inhibitors, Monoamine oxidase inhibitors Antipsychotic drugs: Phenothiazines (Thioridazine, Trifluoperazine), Butyrophenones (Haloperidol) Antiepileptic drugs: Carbamazepine, Oxcarbazepine, Sodium valproate Anticancer agents: Vinca alkaloids (Vincristine, Vinblastine), Platinum compounds (Cisplatin, Carboplatin) Alkylating agents: Intravenous Cyclophosphamide, Melphalan, Ifosfamide Miscellaneous: Methotrexate, Interferon, Levamisole, Pentostatin, Monoclonal antibodies, MDMA, Nicotine Opiates
Increase ADH effect	Antiepileptic drugs: Carbamazepine, Lamotrigine Antidiabetic drugs: Chlorpropamide, Tolbutamide Anticancer agents: Alkylating agents (Intravenous cyclophosphamide) NSAIDS
Drugs affecting water and sodium homeostasis	Diuretics: Thiazides, Indapamide, Amiloride, Loop diuretics
Reset omostat ‡	Antidepressants: Venlafaxine Antiepileptic drugs: Carbamazepine
Vasopressin analogues	Desmopressin, oxytocin, terlipressin, vasopressin

‡ Altered sensitivity to serum osmolality by the hypothalamic osmoreceptors

Causes by Organ System

Cardiovascular	Congestive heart failure
Chemical / poisoning	No underlying causes
Dermatologic	Burns
Drug Side Effect	ACE inhibitors, Ajuga nipponensis makino , Asenapine maleate, Cefpodoxime, Chlorpropamide, Cyclophosphamide, Desmopressin, Diuretics, Duloxetine, Eslicarbazepine acetate, Ethacrynic Acid, Felbamate, Fluvoxamine, Interferon gamma, Ixabepilone, Losartan and Hydrochlorothiazide, Nilotinib,Nivolumab, Nonsteriodal anti-inflammatory drugs , Oxcarbazepine, Pramipexole, Rifaximin, Tiagabine, Tolazamide, Zonisamide, Tolbutamide, Vortioxetine, Brivanib , Cetuximab
Ear Nose Throat	No underlying causes
Endocrine	Addison's disease, Corticosterone methyloxidase type I deficiency , Diabetes mellitus, Diabetic coma, Glucocorticoid deficiency, Familial hyperreninemic hypoaldosteronism type 2, Hypothyroidism, Mineralocorticoid deficiency, Myxedema coma , Syndrome of inappropriate antidiuretic hormone , Thyrotropin deficiency, 18-Hydroxylase deficiency , Familial hypoaldosteronism
Environmental	No underlying causes
Gastroenterologic	Acute liver failure , Cirrhosis, Congenital chloride diarrhea , Diarrhea, Gastrointestinal fistula, Ileus, complicated appendicitis, Necrotizing enterocolitis , Pancreatitis, Peritonitis, Vomiting, Cystic fibrosis
Genetic	18-Hydroxylase deficiency , Bartter Syndrome type 4 , Cystic fibrosis, Familial hypoaldosteronism , Corticosterone methyloxidase type I deficiency , Familial hyperreninemic hypoaldosteronism type 2, Congenital chloride diarrhea
Hematologic	No underlying causes
Iatrogenic	After pituitary surgery, After surgery, Ascitic tap, Gastric drainage, Hypotonic infusions, Pleuracentesis, Tumor lysis syndrome (TLS) associated with pediatric hematologic malignancies, and managed with aggressive intravenous hydration can cause fluid overload (FO) and acute kidney injury (AKI).
Infectious Disease	Malignant boutonneuse fever , Neonatal bacterial meningitis , Peritonitis, influenza and other respiratory viruses, HIV infection, Corona virus infections, community acquired pneumonia from bacterial (streptococcus pneumonia, legionella etc)
Musculoskeletal / Ortho	No underlying causes
Neurologic	Intracranial hemorrhage, Subarachnoid hemorrhage, Pituitary cancer, stroke , Post traumatic brain injury hypopituitarism causing adrenal insufficiency.
Nutritional / Metabolic	Hyperlipidemia, Hyperproteinemia, Hypoalbuminemia, Low sodium diet, Metabolic acidosis, Diabetic coma
Obstetric/Gynecologic	Pregnancy, postpartum in patients with preeclampsia
Oncologic	Pituitary cancer
Opthalmologic	No underlying causes
Overdose / Toxicity	Water intoxication
Psychiatric	Psychogenic polydipsia, Psychosis, Self-induced water intoxication and schizophrenic disorders syndrome
Pulmonary	Cystic fibrosis
Renal / Electrolyte	Acute kidney disease, Chronic kidney disease, Diuresis, Glucosuria, Ketonuria, Nephrotic syndrome, Renal Tubular Acidosis, Tubulointerstitial kidney disease, Bartter Syndrome type 4 , Corticosterone methyloxidase type I deficiency , Renal failure
Rheum / Immune / Allergy	Addison's disease, Nephrotic syndrome
Sexual	Cystic fibrosis
Trauma	Burns
Urologic	No underlying causes
Dental	No underlying causes
Miscellaneous	Beer potomania, Ecstasy abuse , Factitious hyponatremia, Hydration, Massive edema, Pseudohyponatremia, Water Intoxication , Hyperlipidemia, Hyperproteinemia, Hypoalbuminemia, Exercise associated hyponatremia

Causes in Alphabetical Order

18-Hydroxylase deficiency ACE inhibitors Acute kidney disease Acute liver failure Addison's disease After pituitary surgery After surgery Ajuga nipponensis makino Ascitic tap Bartter Syndrome type 4 Beer potomania Burns Chronic kidney disease Cirrhosis Congenital chloride diarrhea Congestive heart failure Corticosterone methyloxidase type I deficiency Cyclophosphamide Cystic fibrosis Desmopressin Diabetes mellitus Diabetic coma Diarrhea Diuresis Diuretics Ecstasy abuse Exercise associated hyponatremia Factitious hyponatremia Familial hypoaldosteronism Familial hyperreninemic hypoaldosteronism type 2 Gastric drainage Gastrointestinal fistula Glucocorticoid deficiency Glucosuria Hydration Hyperlipidemia

Hyperproteinemia Hypoalbuminemia Hypothyroidism Hypotonic infusions Ileus Interferon gamma Intracranial hemorrhage Ketonuria Low sodium diet Malignant boutonneuse fever Massive edema Metabolic acidosis Mineralocorticoid deficiency Myxedema coma Necrotizing enterocolitis Neonatal bacterial meningitis Nephrotic syndrome Nonsteriodal anti-inflammatory drugs Pancreatitis Peritonitis Pituitary cancer Pleuracentesis Pregnancy Pseudohyponatremia Psychogenic polydipsia Psychosis Renal Failure Renal Tubular Acidosis Self-induced water intoxication and schizophrenic disorders syndrome Subarachnoid hemorrhage Syndrome of inappropriate antidiuretic hormone Thyrotropin deficiency Tiagabine Tubulointerstitial kidney disease Vomiting Water Intoxication

References